Veterinary treatment

ABSTRACT

The antibiotic compound M139603 (tetronasin), disclosed in GB-A-2027013 as a growth-promotant in farm animals with activity against Gram-positive bacteria, has now been found to prevent and treat Treponem a hyodysenteriae infections in pigs (swine dysentery).   Analogues of M139603 have the same action. The compound is administered in the pig&#39;s food or water supply.

This invention relates to the treatment of Treponema hyodysenteriae infection in pigs, T. hyodysenteriae being the causative organism of swine dysentery, a debilitating, economically costly and sometimes fatal disease.

Current medicaments include ethacridine lactate, tylosin, erythromycin, tiamulin and certain polyether antibiotics such as salinomycin and lasalocid. It has now been found that the compound known as ICI M139603 or tetronasin, disclosed in GB-A-2 027 013 as being a growth-promoting antibiotic with activity against Grampositive bacteria and coccidia, has surprising levels of activity against T.hyodysenteriae.

Accordingly, one aspect of the invention provides the preparation of a medicament, for use in combatting or preventing Treponema hyodysenteriae infections in pigs, comprising the compound M139603 or physiologically functional equivalents thereof.

A second aspect provides a composition comprising M139603 or physiologically functional equivalents thereof and specifically adapted for use in combatting or preventing Treponema hyodysenteriae infections in pigs.

A third aspect provides a method of combatting or preventing Treponema hyodysenteriae infection in pigs comprising the administration to the pigs of a non-toxic, infection-combatting or infection-preventing amount of M139603 or physiologically functional equivalents thereof.

The compound M139603 is a metabolite produced by at least some strains of Streptomyces longisporoflavus, including the strain which is freely available as deposit NCIB 11426 from the National Collections of Industrial and Marine Bacteria, P.O. Box 31, Aberdeen, Scotland AB9 8DG and as CBL 312.79 from CBS, P.O. Box 273, 3740 Baarn, Netherlands. Its isolation and characteristics are described in GB-A-2 027 013 and in Davies et al, J.C.S. Chem. Comm., 1981, 1073-4.

The term "physiologically functional equivalents of M139603" includes the free acid (M139603 being the sodium salt), salts (especially alkali metal salts), ethers, esters, urethanes, thiourethanes, carbonates, aldehydes and oximes such as are disclosed in EP-A-70 622 (which is incorporated herein by reference) and generally all compounds having the active polyether structure of M139603 with only such modifications thereof which do not diminish its activity to an unacceptable level. The equivalent compounds are preferably compounds of Formula (I): ##STR1## wherein: M+ is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation;

R¹ is a hydrogen atom, an alkyl radical or an optionally substituted phenylalkyl radical; and

R² is a formyl, iminomethyl, hydroxyiminimethyl or aminomethyl radical, or a radical of the formula --CH:NR³, --CH:NOR⁴ or --CH₂ NR⁵ R⁶ wherein R³, R⁴, R⁵ and R⁶ may each be an alkyl or an optionally substituted phenyl or phenylalkyl radical; or

a radical of the formula --CH₂ OR⁷ wherein R is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl radical or an optionally substituted phenylalkyl radical; or

a radical of the formula --CH₂ O.COR⁸ wherein R⁸ is an alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or dialkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl, N,N-dialkylcarbamoylalkyl or optionally substituted phenyl, naphthyl or phenylalkyl radical; or

a radical of the formula --CH₂ O.CO.COR⁹ wherein R⁹ is an amino, mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl radical; or

a radical of the formula --CH₂ O.CX.NR¹⁰ R¹¹ wherein X is an oxygen or sulphur atom and R¹⁰ and R¹¹, which may be the same or different, are each a hydrogen atom, an alkyl radical or an optionally substituted phenyl, naphthyl or phenylalkyl radical;

or, when R¹ is a hydrogen atom or an alkyl radical of 2 or more carbon atoms or an optionally substituted phenylalkyl radical, R² is a hydroxymethyl radical, and wherein each alkyl, alkenyl or alkynyl radical contains up to 6 carbon atoms, and wherein, in each complex radical containing an alkyl part, the said alkyl part contains 1 to 6 carbon atoms, and wherein each cycloalkyl radical or cycloalkyl part of a (cycloalkyl)-alkyl radical contains 3 to 7 carbon atoms.

A particular value for any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ when it is an alkyl radical, or when it is a complex radical containing an alkyl part, is, for example, such an alkyl radical which contains 1 to 3 carbon atoms, or such a complex radical wherein the alkyl part contains 1 to 3 carbon atoms.

A particular optional substituent in R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ or R¹¹ when any of them is an optionally substituted phenyl, naphthyl or phenylalkyl radical is, for example, a halogen atom, a nitro, cyano or hydroxy radical, or an akyl, alkoxy, halogenoalkyl, halogenalkoxy, alkylamino, dialkylamino or alkanoylamino radical, for example such a radical of up to 8 carbon atoms, preferably of up to 4 carbon atoms.

A particular value for R⁷ when it is an alkenyl or alkynyl radical is, for example, such a radical of 2 or 3 carbon atoms.

Particular cations M+ are, for example, the sodium, lithium, potassium, calcium, magnesium, zinc, ammonium, mono-, di-, tri- and tetra-alkylammonium ions wherein each alkyl is of 1 to 10 carbon atoms, and mono-, di- and tri-(hydroxyalkyl)ammonium ions wherein each hydroxyalkyl is of 1 to 10 carbon atoms.

Particular compounds of the invention which are preferred are those compounds of Formula I wherein R¹ is methyl and R² is hydroxymethyl, formyl, methoxy-methyl, propargyloxymethyl, benzoyloxymethyl, 2-bromobenzoyloxymethyl, chloroacetoxymethyl, ethoxalyloxymethyl or N-methylthiocarbomoyloxymethyl.

The fifteen analogues mentioned below in Example 8 are specific Examples.

The following further examples of compounds within the scope of the invention may also be mentioned, referring to the structural formula given above, M+ being sodium and R¹ being methyl (except where indicated):

R²

--CH₂ O.COCH₂ Cl

--CH₂ OCH₂ --(1-bromophenyl)

--CH₂ O(CH₂)₂ NMe₂

--CH₂ O.CONHPh

--CH₂ OH (R¹ is hydrogen)

Such compounds may be made by the methods described in Ep-A-706822.

M139603 or equivalent may be administered to the pigs by any suitable route, preferably orally and especially in their normal feed or drinking water. When presented in the feed, levels as low as 10 ppm have been found to be effective. In a pig which consumes about 6% of its body weight per day under experimental conditions. (e.g. quickly growing hybrids under S.P.F. conditions), this dosage is equivalent to about 0.6 mg/kg body weight, which is very low in comparison with other compounds effective against swine dysentery. Typical food consumption rates on farms vary from 4% (40-50 kg animals) to 5% (animals up to 20 kg). In general, feed levels of 5-200 ppm of M139603 or equivalent are useful, with levels of 10-50 ppm, particularly about 15, 20, 25, 30, 35, 40, 45 or 50 ppm being preferred.

EXAMPLE 1 IN VITRO ACTIVITY

The minimum inhibitory concentration of M139603 was tested in parallel with dimetridazole (May & Baker) and the growth-promoting polyether antibiotic salinomycin (Hoechst) against thirteen strains of T. hyodysenteriae. The results are given in Table 1. Statistical analyses of the MIC results have shown M139603 to have a significantly (p<0.001) lower MIC (mean=0.215 mcg) than salinomycin (mean=0.688 mcg).

EXAMPLE 2 COMPARATIVE EFFICACY OF M139603 AND MONENS IN MICE

Young mice (strain MF-1, Olac Ltd), each weighing 20 grams approximately, given ad lib drinking-water medicated with spectinomycin hydrochloride ("Spectam", Abbotts) at a concentration of 1.25 g/liter on three continuous days before and after the oral administration of an infective dose (0.4×10⁶ cfu per mouse) of T.hyodysenteriae, have been found to be consistently susceptible to the infection. The infection leads to varying degrees of caecitis, the lesions of which are apparent in animals killed on or about the sixth day post-infection. Caecal specimens examined by bacteriological culture techniques applicable for enumeration of organisms reveal the presence of high populations of T.hyodysenteriae. This disease-model was used in experiments to compare the efficacy of M139603 with that of salinomycin, lasalocid and monensin in suppressing the infection.

In this study, the efficacy of M139603 was tested at 25 ppm feed and that of monensin (Eli Lilly) at 50 or 100 ppm. Groups of infected mice, five per group, were offered the drugs in the feed on five continuous days before killing. Caecal materials were subjected to bacteriological examination to enumerate the populations of viable treponemes per gram of material. The results are given in Table 2. Compound M139603 at 25 ppm and monensin at 100 ppm suppressed the infection but the latter drug at 50 ppm proved ineffective since four out of five animals in this group yielded high populations (1.0×10⁵ -1.7×10⁸ cfu/g) of viable treponema with a group mean (log₁₀) of 5.2 cfu/g caecum. The group mean in respect of the unmedicated groups was 7.9 cfu/g.

EXAMPLE 3 COMPARATIVE EFFICACY OF M139603 AND SALINOMYCIN IN MICE

In this study, the efficacy of M139603 was tested at 30 ppm and that of salinomycin at 30, 40 or 60 ppm feed. The mouse-groups and test-procedures were simi-ar to those applied under Example 2 above. The results are given in Table 3. Compound M139603 suppressed the infection. Salinomycin failed to do so, even at 60 ppm.

EXAMPLE 4 COMPARATIVE EFFICACY OF M139603 AND LASALOCID IN MICE

In this study, the efficacy of M139603 was tested at 20 ppm feed and that of lasalocid (Hoffman la Roche) at 20, 40 and 80 ppm. The test procedures were similar to those above except for the size of the inoculum of T.hyodysenteriae (1.2×10⁷ cfu) used in infecting each mouse. The results are given in Table 4. Despite use of high inocula, M139603 at 20 ppm completely suppressed the infection in two mice and markedly reduced the T.hyodysenteriae populations in the other three placed on this drug. The mean (log₁₀) counts of viable treponemes found in the caecal contents of the various groups were: 2.5 cfu/g caecum (139603 at 20 ppm), 7.35 cfu (lasalocid at 20 ppm), 7.45 cfu (lasalocid at 40 ppm), 3.81 cfu (lasalocid at 80 ppm) and 8.50 cfu (unmedicated control). Thus the efficacy of M139803 at 20 ppm could be considered greater than that of lasalocid at 80 ppm.

EXAMPLE 5 EFFICACY OF M139603 IN PREVENTING SWINE DYSENTERY IN PIGS (EXPERIMENTAL INFECTION)

The efficacy of M139603 was tested at 25 ppm feed.

In this studY two groups (Gp.1 and Gp.2) of pigs, six per group, were experimentally infected with a pathogenic strain of T. hyodysenteriae (P18a, IRAD(Institute for Animal Health), Compton, Berks, U.K.) by oro-gastric inoculation of 50 ml of a culture suspension (1×10⁷ cfu/ml) of the organism into each animal. From post-infection day (PID) to PID 35 the animals in Gp. 1 were offered ad lib a feed comprising "Kwikwean" meal (Rank, Hovis, McDougall Research Ltd; containing no antibiotics) incorporated with M139603 at 25 ppm. Gp.2 remained on unmedicated feed throughout the trial. Drug efficacy was measured primarily on the basis of the number of diarrhoea or dysentery days in relation to pig-days within a group and on the average daily weight gain per pig, in each group over the period of the trial. The daily gain was calculated by dividing group gain at end of trial (PID 35) by the total number of pig-days from PID 1 to PID 35. The results, summarised in Table 5, point to the efficacy of M139603 at 25 ppm feed (which provides for a daily drug intake between 1.25-1.55 mg/kg body-weight) in preventing or minimising the incidence of swine dysentery. In the experiment the pigs were exposed to high infective doses of the organism a day before the introduction of the drug. Under normal circumstances preventive dose-regimes are applied on animals at risk and not on those already infected.

EXAMPLE 6 EFFICACY OF M139603 IN PIGS (NATURAL INFECTION)

In this study, eighteen pigs were allocated to three equal groups (Gp.1-3). Feed incorporated with the drug at 25 or 15 ppm was offered to Gp.1 and 2, respectively, on thirty-eight consecutive days commencing six hours pre-infection. Gp.3 remained on unmedicated feed throughout the trial. The pigs were infected with T. hyodysenteriae (strain "P18a") using methods and materials similar to those applied in Example 5. However, seven days following this exposure (post-infection day 7), over a period of seven consecutive days, the pigs in Gp. 1 and 2 were allowed to co-mingle for about two hours each day with some dysenteric "seeder pigs" in a nearby pen. Drug efficacy, as in Example 6, was assessed primarily on the basis of the total number of diarrhoea/dysentery days per group and on the basis of average daily weight gain per pig per group. The findings are summarised in Table 6. The results are indicative of the good efficacy of M139603 even at a level as low as 15 ppm feed in preventing swine dysentery. At this dose-level, the daily drug-intake is unlikely to be more than 0.9 mg/kg/body-weight, if daily feed is calculated at 6% of a pig's body-weight. The diarrhoea score of 6.1% against Gp.1 (25 ppm feed) was result of one of the six animals in group developing a transient dysentery. This result cannot be considered discouraging, since preventive dose regimes with commercially available anti-swine dysentery drugs have not always suppressed the infection.

EXAMPLE 7 EFFICACY OF M139603 IN PIGS AT LOW DOSES

In this experiment twenty-four pigs were split into four equal groups (Gp. 1-4). Gp. 1 and 2 were offered the drug at 15 or 10 ppm feed on forty-two consecutive days, commencing six hours pre-infection. Gp. 3 (infected) and Gp. 4 (uninfected) remained on unmedicated feed throughout. The infection procedures with T. hyodysenteriae (P18a) were similar to those applied above. Only three groups, Gp. 1, 2 and 3 were infected. Gp. 4 remained uninfected in a well-isolated pen throughout the trial period. Three days following the initial exposure to the infection (post-infection day 3), over a period of five continuous days, the pigs in Gp. 1, 2 and 3 were allowed to co-mingle with dysenteric "seeder pigs" housed in a separate pen. Drug efficacy was measured using the criteria applied in the Examples 5 and 6. The results are summarised in Table 7. Significant weight gain differences, by post-infection day 21, were found between the medicated (Gp.1 and 2) and the unmedicated, infected group (Gp. 3). Thereafter, the differences narrowed, primarily due to the placement of Gp. 3 on tiamulin to prevent further weight losses, and consequent deaths. Despite the number of diarrhoea days observed for Gp. 1 (6.8%) and Gp. 2 (11.9%) during the forty-two days of medication, the average daily weight-gain per pig on each of these two groups exceeded that recorded for pigs in the uninfected, unmedicated group (GP. 4).

EXAMPLE 8 The in vitro and in vivo inhibitory activity of 15 semi-synthetic analogues of M139603

The fifteen compounds were compounds of Formula (I): ##STR2## wherein, M+ is sodium, R¹ is methyl and R² is as follows:

    ______________________________________                                         Analogue No   R.sup.2                                                          ______________________________________                                         CH.sub.2 OMe                                                                   2                                                                              CH.sub.2 O.COPh                                                                3                                                                              CH.sub.2 O.CONHMe                                                              4                                                                              CH.sub.2 O.CONH-(4-bromophenyl)                                                5                                                                              CH.sub.2 O.CONH.sup.n Bu                                                       6                                                                              CH.sub.2 O.CSNHMe                                                              7                                                                              CH.sub.2 O.COCH.sub.2 Br                                                       8                                                                              CH.sub.2 O.CO.COOEt                                                            9                                                                              CH.sub.2 O.CO(CH.sub.2).sup.2 COOH                                             10                                                                             CH:NOH                                                                         11                                                                             CH.sub.2 O.sup.n Bu                                                            12                                                                             CH.sub.2 OCH.sub.2 -C = CH                                                     13                                                                             CH.sub.2 OCH.sub.2 Ph                                                          14                                                                             CH.sub.2 O.COOEt                                                               15                                                                             CH = N-N(H)-(2,4-dinitrophenyl)                                                ______________________________________                                    

T. hyodysenteriae strain "P18a" was used in both in vitro and in vivo tests as above.

Minimum inhibitory concentration test: An agar-dilution M.I.C. test procedure was applied in the study. The susceptibility of the bacterial strain was tested against a range of dilutions (0.3 mg; 0.1 mg; 0.03 mg; 0.01 mg and 0.003 mg/l medium) of each compound incorporated in plates of Isosensitest agar (Oxoid CM471) with 5% added sheep-blood. The plates, `spot-inoculated` (Steer's type multipoint inoculator) with a standard culture-suspension of the test strain, were incubated anaerobically at 39° C. for 48-72 hours before reading the results. The M.I.C. of each compound was read as the lowest concentration yielding no growth (no haemolysis) or a hazy growth (faint haemolysis) on the site of the spot-inoculation. The results are shown in Table 8.

In vivo test in mice: this test was similar to that described in Example 2 above, except that approximately 25g mice were infected with 1.0×10⁷ cfu/ml of P18a and the mice were killed at Day 4 post-infection. Drug efficacy was scored as "good", "moderate" or "inactive" if 80%-100%, 40%-60%, and <40% respectively of individuals in a treated group yielded less than 1.0×10² cfu/g of caecal contents. The results are shown in Table 9.

                  TABLE 1                                                          ______________________________________                                         Minimum inhibitory concentration (MIC) values                                  of M139603 against T. hyodysenteriae in                                        comparison with salinomycin and dimetridazole.                                 ISOLATE      MIC μg/ml of                                                   NO.     M139803  SALINOMYCIN  DIMETRIDAZOLE                                    ______________________________________                                         S82/6   0.2       0.75        30                                               S82/7   0.2       0.75        30                                               S83/1   <0.1      0.75        30                                               S83/2   0.5      1.0          3.0                                              S83/5   <0.1     <0.1         3.0                                              S85/1   0.2       0.75        30                                               S85/2   0.2      1.0          10                                               S85/3   0.2       0.75        10                                               S85/8   0.2       0.75        3.0                                              S85/9   <0.1     0.5          5.0                                              S86/1   <0.1     <0.1         <0.5                                             S86/2   0.2      0.75         10                                               B78     0.5      1.0          3.0                                              Mean     0.215   0.68         12.88                                            (13 strains)                                                                   ______________________________________                                    

                                      TABLE 2                                      __________________________________________________________________________     Activity of M139803 in comparison with monensin                                against T.hyodysenteriae in experimentally                                     infected mice                                                                                                VIABLE                                                                         TREPONEMES                                                                     PER GRAM                                         GROUP MOUSE DRUG                                                                            DOSE-LEVEL                                                                             MEDICATION                                                                              CAECUM &                                         NO.          (ppm. feed)                                                                            PERIOD   CONTENTS                                         __________________________________________________________________________     1 1   M-139603                                                                              25 ppm  5 days   negative**                                         2   M-139603                                                                              25 ppm  5 days   negative**                                         3   M-139603                                                                              25 ppm  5 days   negative**                                         4   M-139603                                                                              25 ppm  5 days   negative**                                         5   M-139603                                                                              25 ppm  5 days   negative**                                         Mean                                                                           (log.sub.10)                0                                                2 1   Monensin                                                                              50 ppm  5 days   1.74 × 10.sup.8                              2   Monensin                                                                              50 ppm  5 days   2.90 × 10.sup.7                              3   Monensin                                                                              50 ppm  5 days    1.0 × 10.sup.5                              4   Monensin                                                                              50 ppm  5 days   negative                                           5   Monensin                                                                              50 ppm  5 days    2.0 × 10.sup.5                              Mean                                                                           (log.sub.0)                 5.2                                              3 1   Monensin                                                                              100 ppm 5 days   negative**                                         2   Monensin                                                                              100 ppm 5 days   negative**                                         3   Monensin                                                                              100 ppm 5 days   negative**                                         4   Monensin                                                                              100 ppm 5 days   negative**                                         5   Monensin                                                                              100 ppm 5 days   negative**                                         Mean                                                                           (log.sub.10)                0                                                4 1   Unmedicated                                                                           --      5 days   1.01 × 10.sup.8                              2   Unmedicated                                                                           --      5 days    3.2 × 10.sup.7                              3   Unmedicated                                                                           --      5 days    5.0 × 10.sup.6                              4   Unmedicated                                                                           --      5 days   3.28 × 10.sup.8                              5   Unmedicated                                                                           --      5 days   >9.9 × 10.sup.8                              Mean                                                                           (log.sub.10)                7.94                                             __________________________________________________________________________      **Limit of detection = <1.0 × 10.sup.2                             

                                      TABLE 3                                      __________________________________________________________________________     Activity of M139603 in comparison with                                         salinomycin against T. hyodysenteriae in                                       experimentally infected mice.                                                                                VIABLE                                                                         TREPONEMES                                                                     PER GRAM                                         GROUP MOUSE DRUG                                                                            DOSE LEVEL                                                                             MEDICATION                                                                              CAECUM &                                         NO.          (ppm feed)                                                                             PERIOD   CONTENTS                                         __________________________________________________________________________     1 1   M139603                                                                               30 ppm  5 days   negative                                           2   M139603                                                                               30 ppm  5 days   negative                                           3   M139603                                                                               30 ppm  5 days   negative                                           4   M139603                                                                               30 ppm  5 days   negative                                           5   M139603                                                                               30 ppm  5 days   negative                                           Mean                                                                           (log.sub.10)                0                                                2 1   Salinomycin                                                                           30 ppm  5 days   negative                                           2   Salinomycin                                                                           30 ppm  5 days   negative                                           3   Salinomycin                                                                           30 ppm  5 days   6.0 × 10.sup.6                               4   Salinomycin                                                                           30 ppm  5 days   6.0 × 10.sup.6                               5   Salinomycin                                                                           30 ppm  5 days   5.4 × 10.sup.5                               Mean                                                                           (log.sub.10)                3.86                                             3 1   Salinomycin                                                                           40 ppm  5 days   6.0 × 10.sup.6                               2   Salinomycin                                                                           40 ppm  5 days   1.8 × 10.sup.6                               3   Salinomycin                                                                           40 ppm  5 days   1.6 × 10.sup.5                               4   Salinomycin                                                                           40 ppm  5 days   1.8 × 10.sup.6                               5   Salinomycin                                                                           40 ppm  5 days   4.3 × 10.sup.5                               Mean                                                                           (log.sub.10)                6.03                                             4 1   Salinomycin                                                                           60 ppm  5 days   1.3 × 10.sup.7                               2   Salinomycin                                                                           60 ppm  5 days   2.0 × 10.sup.4                               3   Salinomycin                                                                           60 ppm  5 days   1.0 × 10.sup.6                               4   Salinomycin                                                                           60 ppm  5 days   1.0 × 10.sup.4                               5   Salinomycin                                                                           60 ppm  5 days   1.5 × 10.sup.6                               Mean                                                                           (log.sub.10)                5.52                                             5 1   Unmedicated                                                                           --      5 days   4.3 × 10.sup.6                               2   Unmedicated                                                                           --      5 days   2.0 × 10.sup.7                               3   Unmedicated                                                                           --      5 days   4.0 × 10.sup.7                               4   Unmedicated                                                                           --      5 days   1.9 × 10.sup.5                               5   Unmedicated                                                                           --      5 days   2.1 × 10.sup.7                               Mean                                                                           (log.sub.10)                6.83                                             __________________________________________________________________________

                                      TABLE 4                                      __________________________________________________________________________     Activity of M139603 in comparison with lasalocid                               against T. hyodysenteriae in experimentally                                    infected mice                                                                                              VIABLE                                                                         TREPONEMES                                                                     PER GRAM                                           GROUP MOUSE                                                                               DOSE-LEVEL                                                                             MEDICATION                                                                              CAECAL                                             DRUG NO    (ppm. feed)                                                                            PERIOD   CONTENTS                                           __________________________________________________________________________     1 1   M139603                                                                             20 ppm  5 days   0                                                    2   M139603                                                                             20 ppm  5 days   4.3 × 10.sup.3                                 3   M139603                                                                             20 ppm  5 days   0                                                    4   M139603                                                                             20 ppm  5 days   3.0 × 10.sup.2                                 5   M139603                                                                             20 ppm  5 days   1.0 × 10.sup.2                                 Mean                                                                           (log.sub.10)              1.62                                               2 1   Lasalocid                                                                           20 ppm  5 days   3.2 × 10.sup.8                                 2   Lasalocid                                                                           20 ppm  5 days   1.1 × 10.sup.4                                 3   Lasalocid                                                                           20 ppm  5 days   3.2 × 10.sup.8                                 4   Lasalocid                                                                           20 ppm  5 days   2.9 × 10.sup.7                                 5   Lasalocid                                                                           20 ppm  5 days   1.7 × 10.sup.8                                 Mean                                                                           (log.sub.10)              7.35                                               3 1   Lasalocid                                                                           40 ppm  5 days   3.0 × 10.sup. 6                                2   Lasalocid                                                                           40 ppm  5 days   1.4 × 10.sup.8                                 3   Lasalocid                                                                           40 ppm  5 days   2.1 × 10.sup.8                                 4   Lasalocid                                                                           40 ppm  5 days   1.7 × 10.sup.7                                 5   Lasalocid                                                                           40 ppm  5 days   1.2 × 10.sup.7                                 Mean                                                                           (log.sub.10)              7.45                                                 1   Lasalocid                                                                           80 ppm  5 days   4.0 × 10.sup.4                                 2   Lasalocid                                                                           80 ppm  5 days   0                                                    3   Lasalocid                                                                           80 ppm  5 days   1.0 × 10.sup.6                                 4   Lasalocid                                                                           80 ppm  5 days   1.3 × 10.sup.5                                 5   Lasalocid                                                                           80 ppm  5 days   2.3 × 10.sup.3                                 Mean                                                                           (log.sub.10               3.81                                               5 1   Lasalocid Unmedicated                                                                       5 days   4.4 × 10.sup.8                                 2   Lasalocid Unmedicated                                                                       5 days   1.1 × 10.sup.8                                 3   Lasalocid Unmedicated                                                                       5 days   7.2 × 10.sup.8                                 4   Lasalocid Unmedicated                                                                       5 days   2.5 × 10.sup.8                                 5   Lasalocid Unmedicated                                                                       5 days   3.4 × 10.sup.8                                 Mean                                                                           (log.sub.10)              8.50                                               __________________________________________________________________________

                  TABLE 5                                                          ______________________________________                                         Summary of results of experiment at 25 ppm feed.                                                 Group 1 Group 2                                                                Medicated                                                                              Unmedicated                                          ______________________________________                                         Number pigs/group   6         6                                                Drug in feed (ppm)  25        0                                                Period (days) of continuous daily                                                                  35                                                         medication commencing 24 hour post-                                            infection                                                                      Ave. daily drug-intake (mg/kg                                                  body-wt) based on                                                              (i)  ave daily feed-intake at                                                                          1.25      0                                                 5% animal's body-wt.                                                      (ii) ave daily feed-intake at                                                                          1.5       0                                                 6% animal's body-wt.                                                      Mortality (+ culls) 0         2                                                Number diarrhoea/dysentery days                                                                    27        75                                               (PID 1-35)                                                                     Percent diarrhoea/dysentery days                                                                   12.9      46.3                                             (PID 1-35)                                                                     Group weight (kg) at start                                                                         112       108.5                                            of experiment                                                                  Average weight at start                                                                            18.8      18.1                                             of experiment                                                                  Group weight (kg) at termination                                                                   243       137                                              Average weight at termination                                                                      40.5      34.25                                            Number pigs days at termination                                                                    210       162                                              Averae daily weight-gain (kg)                                                                      0.62      0.17                                             ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                         Summary of results of experiment at 15 or 25 ppm feed                                             Group Group   Group                                                            1     2       3                                             ______________________________________                                         Number pigs/group    6       6       6                                         Drug in feed (ppm)   25      15      0                                         No. days medication commencing                                                                      38      38      0                                         6 hrs pre-infection                                                            Ave. daily drug-intake (mg/kg                                                  body-wt), based on                                                             (i)  ave daily feed-     1.25    0.75  0                                            intake at 5% animal's body-wt.                                            (ii) ave daily feed-intake at 6%                                                                        1.5     0.9   0                                            animal's body-wt.                                                         Mortality (+ culls)  0       0       1                                         Number diarrhoea/dysentery days                                                                     14      0       81                                        (pi 1 to 38)                                                                   Percent diarrhoea/dysentery days                                                                    6.1     0       37.9                                      (pi 1 to 38)                                                                   Group weight (kg) at start: day 3                                                                   65.7    65.5    65.1                                      pre-infecton                                                                   Average weight (kg) at day 3                                                                        10.95   10.95   10.85                                     pre-infection                                                                  Group weight (kg) at end                                                                            246.5   246.5   158                                       Average weight (kg) at end                                                                          41.0    41.0    26.3                                      Number pig days at end                                                                              228     228     214                                       Average daily weight-gain (kg)                                                                      0.72    0.72    0.39                                      ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                         Summary of results of experiment at 10 or 15 ppm                                              GROUP                                                                          1     2       3       4                                         ______________________________________                                         No. pigs/group   6       6       6     6                                       Drug in feed (ppm)                                                                              15      10      0     0                                       Average daily drug intake mg/                                                  kg body-wt.) based on:-                                                        (i)  ave. daily feed intake at                                                                      0.75    0.5   0     0                                          5% body-weight                                                            (ii) ave. daily feed intake at                                                                      0.90    0.6   0     0                                          6% body-weight                                                            Mortality (+ culls)                                                                             0       0       0     0                                       No. diarrhoea/dysentery days                                                   days from:-                                                                    (i)  post-infection day 1 to 21                                                                     5       6     66    0                                          (126 pig-days)                                                            (ii) post-infection day 1 to 42                                                                     17      30    NA    0                                          (252 pig-days)                                                            Percent diarrhoea/dysentery                                                    days from:-                                                                    (i)  post-infection day 1 to 21                                                                     4       4.8   2.4   0                                     (ii) post-infection day 1 to 42                                                                     6.8     11.9  NA    0                                     Group weight at start                                                                           63.7    66.0    64.0  63.2                                    (day 4 pre-infection)                                                          Ave. weight at start                                                                            10.6    11.0    10.7  10.5                                    (day 4 pre-infection)                                                          Group weight on:-                                                              (i)  post-infection day 21                                                                          153.7   161.0 76.4  151.8                                 (ii) post-infection day 43                                                                          225.5   265.0 181.0 250.9                                      (1 day from withdrawal                                                         of medication)                                                            (iii)                                                                               post-infection day 57                                                                          327.5   3l9.5 248.5 337.5                                      (15 days from with-                                                            drawal of medication)                                                     No. pig days from                                                              (i)  pre-infection day 4 to                                                                         162     162   162   162                                        post-infection day 22                                                     (ii) post-infection day 23                                                                          258     258   258   258                                        to 43                                                                     (iii)                                                                               post-infection day 44                                                                          342     342   342   342                                        to 57                                                                     Ave. daily weight-gain from:-                                                  (i)  day 4 pre-infection to                                                                         0.56    0.59  0.08  0.55                                       day 22 post-infection                                                     (ii) post-infection day 23                                                                          0.81    0.83  0.83  0.79                                       to 43, inclusive                                                          (iii)                                                                               post-infection day 44                                                                          0.86    0.65  0.80  1.03                                       to 57, inclusive                                                          ______________________________________                                          Explanatory: NA = Not Applicable. Group was placed on tiamulin treatment       from postinfection day 22-26                                             

                  TABLE 8                                                          ______________________________________                                         COMPOUND       M.I.C. (mg/l)                                                   ______________________________________                                         M139603        0.01                                                            Analogue 1     0.03                                                            Analogue 2     0.01                                                            Analogue 3     0.1                                                             Analogue 4     0.03                                                            Analogue 5     0.03                                                            Analogue 6     0.03                                                            Analogue 7     0.03                                                            Analogue 8      0.003                                                          Analogue 9     >0.03                                                           Analogue 10    0.01                                                            Analogue 11    0.01                                                            Analogue 12     0.003                                                          Analogue 13    0.01                                                            Analogue 14    0.03                                                            Analogue 15    >0.3                                                            ______________________________________                                    

                  TABLE 9                                                          ______________________________________                                                     Drug-level                                                         Compound    (ppm feed)       Activity                                          ______________________________________                                         Analogue 1  20               good                                              Analogue 2  10               inactive                                                      20               good                                              Analogue 8  10               moderate                                                      20               moderate                                          Analogue 10 10               moderate                                                      20               moderate                                          Analogue 12 10               moderate                                                      12               active                                                        20               active                                                        24               active                                            ______________________________________                                     

What is claimed is:
 1. A method of combatting a Treponema hyodysenteriae infection in a pig having said infection comprising orally administering to a pig having said infection an effective infection combatting amount of tetronasin or physiologically acceptable salt thereof.
 2. A method of preventing a Treponema hyodysenteriae infection in a pig in need thereof, which comprises orally administering to said pig an effective Treponema hyodysenteriae infection prevention amount of tetronasin or physiologically acceptable salt thereof.
 3. A method of combatting a Treponema hyodysenteriae infection in a pig, which comprises the suitable oral administration to a pig in need thereof of an effective amount of the compounds of formula (I): ##STR3## wherein: M+ is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation;R¹ is a hydrogen atom, an alkyl radical or an optionally substituted phenylalkyl radical; and is a formyl, iminomethyl, hydroxyiminimethyl or aminomethyl radical, or a radical of the formula --CH:NR³, --CH:NOR⁴ or --CH₂ NR⁵ R⁶ wherein R³, R⁴, R⁵ and R⁶ may each be an alkyl or an optionally substituted phenyl or phenylalkyl radical; or a radical of the formula --CH₂ OR⁷ wherein R⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl radical or an optionally substituted phenylalkyl radical; or a radical of the formula --CH₂ O.COR⁸ wherein R⁸ is an alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl, N,N-dialkylcarbamoylalkyl or optionally substituted phenyl, naphthyl or phenylalkyl radical; or a radical of the formula --CH₂ O.CO.COR⁹ is an amino, mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl radical; or a radical of the formula --CH₂ O.CX.NR¹⁰ R¹¹ wherein X is an oxygen or sulphur atom and R¹⁰ and R¹¹, which may be the same or different, are each a hydrogen atom, an alkyl radical or an optionally substituted phenyl, naphthyl or phenylalkyl radical; or, when R¹ is a hydrogen atom or an alkyl radical of 2 or more carbon atoms or an optionally substituted phenylalkyl radical, R² is a hydroxymethyl radical, and wherein each alkyl, alkenyl or alkynyl radical contains up to 6 carbon atoms, and wherein, in each complex radical containing an alkyl part, the said alkyl part contains 1 to 6 carbon atoms, and wherein each cycloalkyl radical or cycloalkyl part of a (cycloalkyl)-alkyl radical contains 3 to 7 carbon atoms and wherein the optional substituent in the optionally substituted phenyl, naphathyl or phenylalkyl radical is a halogen atom, a nitro, cyano or hydroxy radical, or an alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, alkylamino, dialkylamino or alkanoylamino radical of up to 8 carbon atoms. 